The present invention relates to medicaments for the alleviation or treatment of symptoms based on ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system, disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia, and other myocardial ischemia-reperfusion injury, and further symptoms due to disorders of transplanted organs at the time of organ transplants, temporary blockage of the blood flow in organs at the time of surgery, etc. or symptoms derived from seizures, epilepsy, migraine, etc.
The present invention further relates to novel piperidine derivatives, tetrahydropyridine derivatives, piperazinodiphenylether derivatives, and piperazino-diphenylmethane derivatives useful for the alleviation or treatment of symptoms based on aforementioned ischemic diseases and intermediates for the synthesis of aforementioned compounds.
In cellular disorders caused by advanced ischemia, the depletion of ATP, the fall in the pH in the cells, and the destruction of the mechanism for maintenance of the energy-dependent ionhomeostasis inside and outside the cell cause the accumulation of a large amount of intracellular divalent Ca ions (Ca2+) (Ca2+ overload). It is believed that the Ca2+ overload causes functional disorders in the mitochondria and randomly activates various enzyme reactions and invites further Ca2+ overload to cause a repeated vicious cycle and in the end causes irreparable damage to the cell wall and cell death [F. B. Meyer: Brain Res. Rev., 14, 227 (1989); E. Boddeke et al.: Trends Pharmacol. Sci., 10, 397 (1989)].
Medicament for suppressing cytotoxic Ca2+ overload are considered useful for the alleviation or treatment of various ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia and myocardial ischemia-reperfusion injury, and further disorders of transplanted organs at the time of organ transplants and temporary blockage of the blood flow in organs at the time of surgery, however, no medicament with sufficient activity has yet been obtained.
In consideration of the state of the prior art, the objective of the present invention is to provide medicaments which have the powerful action of suppressing cytotoxic Ca2+ overload for the alleviation and treatment without side effects of symptoms based on ischemic diseases or symptoms derived from seizures, epilepsy, migraine, etc.
Another objective of the present invention is to provide novel compounds and their salts useful as the medicaments and intermediates for synthesizing the same.
The present inventors screened compounds by evaluating the inhibitory effects on the non-L type Ca2+ channel and Na+ channel reported to be involved in the mechanism of cause of the Ca2+ overload. [P. J. Pauwels et al., Life Science, 48, 1881 (1991)].
As a result, we found that compounds of the general formula (I): 
wherein, Q represents a group having the formula:
Rxe2x80x94Axe2x80x94Bxe2x80x94
in which R represents a hydrogen atom, substituted or unsubstituted phenyl group, substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group,
A represents a connecting bond, a cycloalkylene group, an alkenylene group which may be substituted by a lower alkyl group, a dialkoxymethylene group, or a hydroxyiminomethylene group, and
B represents an alkylene group which may be substituted by a hydroxyl group or an alkoxy group;
a group having the formula. 
xe2x80x83in which R1 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group; or
a group having the formula: 
xe2x80x83in which R2 represents a hydrogen atom, a halogen atom,: an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group;
X represents an oxygen atom or a methylene group,
the substitution of X for the benzene ring being in an ortho, meta, or para position,
E and Y may be the same or different from each other and represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom,
the dotted line shows the presence or absence of a bond, when said dotted line shows the presence of a bond, Z represents a carbon atom, and when said dotted line shows the absence of a bond, Z represents CH or a nitrogen atom have powerful inhibitory actions on one type of the non-L type Ca2+ channel, that is, the T-type Ca2+ channel, and Na+ channel and are effective in various types of animal disease models and thereby completed the present invention.
Flunarizine which is used as an agent for improvement of the brain circulation [P. J. Pauwels et al.; Life Science, 48, 1881 (1991); G. E. Billman; Eur. J. Pharmacol., 212, 231 (1992)) suffers from the problem that it causes as a side effect the onset of symptoms of Parkinson""s disease due to its action of blocking dopamine D2 receptors. This is a major defect in its use. The compounds of the general formula (I) of the present invention, however, were found to have an extremely low affinity for the dopamine D2 receptors causing the side effects of flunarizine.
In the present invention, ischemic diseases include cerebral ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis, and other functional and organic diseases of the brain, ischemic cardiac diseases, for example, variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia and other myocardial ischemia-reperfusion injury, and also disorders of transplanted organs at the time of organ transplants, and temporary blockage of the blood flow in organs at the time of surgery.
The compounds having the general formula (I) of the present invention include compounds of the following general formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and (Ti).
In the general formula (Ia): 
wherein, Q represents a group having the formula Rxe2x80x94Axe2x80x94Bxe2x80x94, the formula: 
or the formula: 
and A, B, E, R, R1, R2X, and Y are as defined above, preferable examples of substituents for the substituted or unsubstituted phenylgroup, substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group represented by R include a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, a hydroxyl group, a C1-C5 alkokyl group which may be branched such as a methoxy group and an ethoxy group, and a C1-C5 alkyl group which may be branched and may be substituted by a halogen atom, such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of a halogen atom of the C1-C5 alkyl group which may be branched and may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
Examples of the cycloalkylene group represented by A include a 1,1-cyclopropylene group, a 1,2-cyclopropylene group, a 1,1-cyclobutylene group, a 1,1-cyclopentylene-group, a 1,1-cyclohexylene group, etc., preferably a C3-C6 cycloalkylene group, particularly preferably a 1,1-cyclopropylene group or a 1,2-cyclopropylene group; preferable examples of the alkenylene group of the alkenylene group which may be substituted by a lower alkyl group include, preferably a C2-C4 alkenylene group such as a vinylene group and a butadienylene group, particularly preferably a vinylene group; preferable examples of the lower alkyl group of the alkenylene group which may be substituted by a lower alkyl group include a methyl group, ethyl group, propyl group, or isopropyl group; preferable examples of the alkoxyl group of the dialkoxymethylene group include a C1-C5 alkoxy group which may be branched such as a methoxy group and an ethoxy group; and, further, the dialkoxymethylene group may be a cyclic acetal such as an ethylene acetal.
Preferable examples of the alkylene group of the alkylene group which may be substituted by a hydroxyl group or an alkoxy group represented by B include preferably a C1-C6 alkylene group which may be branched such as a methylene group, dimethylene group, trimethylene group, tetramethylene group, methylmethylene group, propylene group, cyclopropylmethylene group, etc., particularly preferably a methylene group, dimethylene group, tetramethylene group, or cyclopropylmethylene group. Preferable examples of the alkoxy group of the alkylene group which may be substituted by an alkoxy group include a C1-C5 alkoxy group which may be branched, such as a methoxy group and an ethoxy group.
Preferable examples of the halogen atom represented by R1 or R2 include a fluorine atom, a chlorine atom, or a bromine atom; preferable examples of the alkyl group which may be substituted by a halogen include C1-C5 alkyl group which may be branched, such as a methyl group, an ethyl group, and a trifluoromethyl group; and preferable examples of the alkoxy group include a C1-C5 alkoxy group which may be branched, such as a methoxy group and an ethoxy group. Preferable examples of the halogen atom of the alkyl group which may be substituted by a halogen-atom include a fluorine atom, chlorine atom, and bromine atom.
Preferable examples of the halogen atom represented by E or Y include a fluorine atom, chlorine atom, and bromine atom may be mentioned; preferable examples of the alkoxy group include a C1-C5 alkoxyl group which may be branched, such as a methoxy group and an ethoxy group; and preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched, such as a methyl group, ethyl group, trifluoromethyl group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, chlorine atom, and bromine atom.
When X is an oxygen atom, the substitution of x for the benzene ring is in an ortho, meta, or para position, preferably, a para position.
When X is a methylene group, the substitution of X for benzene ring is in an ortho, meta, or para position, preferably a meta or para position.
In the general formula (Ib): 
Q represents a group having the formula Rxe2x80x94Axe2x80x94Bxe2x80x94, the formula: 
or the formula: 
and A, B, E, R, R1, R2, X, and Y are as defined above, preferable examples of substituents for the substituted or unsubstituted phenyl group, substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group represented by R include a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, a hydroxyl group, a C1-C5 alkokyl group which may be branched such as a methoxy group and an ethoxy group, and a C1-C5 alkyl group which may be branched and may be substituted by a halogen atom, such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of a halogen atom of the C1-C5 alkyl group which may be branched and may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
Examples of the cycloalkylene group represented by A include a 1,1-cyclopropylene group, a 1,2-cyclopropylene group, a 1,1-cyclobutylene group, a 1,1-cyclopentylene group, a 1,1-cyclohexylene group, etc., preferably a C3-C6 cycloalkylene group, particularly preferably a 1,1-cyclopropylene group or a 1,2-cyclopropylene group; preferable examples of the alkenylene group of the alkenylene group which may be substituted by a lower alkyl group include, preferably a C2-C4 alkenylene group such as a vinylene group and a butadienylene group, particularly preferably a vinylene group; preferable examples of the lower alkyl group of the alkenylene group which may be substituted by a lower alkyl group include a methyl group, ethyl group, propyl group, or isopropyl group; preferable examples of the alkoxyl group of the dialkoxymethylene group include a C1-C5 alkoxy group which may be branched such as a methoxy group and an ethoxy group; and, further, the dialkoxymethylene group may be a cyclic acetal such as an ethylene acetal.
Preferable examples of the alkylene group of the alkylene group which may be substituted by a hydroxyl group or an alkoxy group represented by B include preferably a C1-C6 alkylene group which may be branched such as a methylene group, dimethylene group, trimethylene group, tetramethylene group, methylmethylene group, propylene group, cyclopropylmethylene group, etc., particularly preferably a methylene group, dimethylene group, tetramethylene group, or cyclopropylmethylene group. Preferable examples of the alkoxy group of the alkylene group which may be substituted by an alkoxy group include a C1-C5 alkoxy group which may be branched, such as a methoxy group and an ethoxy group.
Preferable examples of the halogen atom represented by R1 or R2 include a fluorine atom, a chlorine atom, or a bromine atom; preferable examples of the alkyl group which may be substituted by a halogen include C1-C5 alkyl group which may be branched, such as a methyl group, an ethyl group, and a trifluoromethyl group; and preferable examples of the alkoxy group include a C1-C5 alkoxy group which may be branched, such as a methoxy group and an ethoxy group. Preferable examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, chlorine atom, and bromine atom.
Preferable examples of the halogen atom represented by E or Y include a fluorine atom, chlorine atom, and bromine atom may be mentioned; preferable examples of the alkoxy group include a C1-C5 alkoxyl group which may be branched, such as a methoxy group and an ethoxy group; and preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched, such as a methyl group, ethyl group, trifluoromethyl group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, chlorine atom, and bromine atom.
When X is an oxygen atom, the substitution of X for the benzene ring is in an ortho, meta, or para position, preferably a para position.
When X is a methylene group, the substitution of X for the benzene ring is in an ortho, meta, or para position, preferably a meta or para position.
In the general formula (IC): 
Q represents a group of the formula Rxe2x80x94Axe2x80x94Bxe2x80x94, the formula: 
or the formula; 
and A, B, E, R, R1, R2, X, and Y are as defined above, preferable examples of substituents for the substituted or unsubstituted phenyl group, substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group represented by R include a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, a hydroxyl group, a C1-C5 alkokyl group which may be branched such as a methoxy group and an ethoxy group, and a C1-C5 alkyl group which may be branched and may be substituted by a halogen atom, such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of a halogen atom of the C1-C5 alkyl group which may be branched and may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
Examples of the cycloalkylene group represented by A include a 1,1-cyclopropylene group, a 1,2-cyclopropylene group, a 1,1-cyclobutylene group, a 1,1-cyclopentylene group, a 1,1-cyclohexylene group, etc., preferably a C3-C6 cycloalkylene group,,particularly preferably a 1,1-cyclopropylene group or a 1,2-cyclopropylene group; preferable examples of the alkenylene group of the alkenylene group which may be substituted by a lower alkyl group include, preferably a C2-C4 alkenylene group such as a vinylene group and a butadienylene group, particularly preferably a vinylene group; preferable examples of the lower alkyl group of the alkenylene group which may be substituted by a lower alkyl group include a methyl group, ethyl group, propyl group, or isopropyl group; preferable examples of the alkoxyl group of the dialkoxymethylene group include a C1-C5 alkoxy group which may be branched such as a methoxy group and an ethoxy group; and, further, the dialkoxymethylene group may be a cyclic acetal such as an ethylene acetal.
Preferable examples of the alkylene group of the alkylene group which may be substituted by a hydroxyl group or an alkoxy group represented by B include, preferably a C1-C6 alkylene group which may be branched such as a methylene group, dimethylene group, trimethylene group, tetramethylene group, methylmethylene group, propylene group, cyclopropylmethylene group, etc., particularly preferably a methylene group, dimethylene group, tetramethylene group, or cyclopropylmethylene group. Preferable examples of the alkoxy group of the alkylene group which may be substituted by an alkoxy group include a C1-C5 alkoxy group which may be branched, such as a methoxy group and an ethoxy group.
Preferable examples of the halogen atom represented by R1 or R2 include a fluorine atom, a chlorine atom, or a bromine atom; preferable examples of the alkyl group which may be substituted by a halogen include C1-C5 alkyl group which may be branched, such as a methyl group, an ethyl group, and a trifluoromethyl group; and preferable examples of the alkoxy group include a C1-C5 alkoxy group which may be branched, such as a methoxy group and an ethoxy group. Preferable examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, chlorine atom, and bromine atom.
Preferable examples of the halogen atom represented by E or Y include a fluorine atom, chlorine atom, and bromine atom may be mentioned; preferable examples of the alkoxy group include a C1-C5 alkoxyl group which may be branched, such as a methoxy group and an ethoxy group; and preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched, such as a methyl group, ethyl group, trifluoromethyl group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, chlorine atom, and bromine atom.
The substitution of X for the benzene ring may be in an ortho, meta, or para position, preferably a meta or para position.
In the general formula (Id): 
R3 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group, R4 and R5 are the same or different from each other and represent a hydrogen atom or a lower alkyl group, or R4 and R5 are taken together to represent xe2x80x94Oxe2x80x94, R6 represents a hydrogen atom, a hydroxyl group, an alkoxy group, or an alkyl group, n is an integer of 1 to 6, and E, X, and Y are as defined above, preferable examples of the halogen atom represented by R3 include a fluorine atom, a chlorine atom and a bromine atom; preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group and a trifluoromethyl group; and preferable examples of the alkoxyl group include a C1-C5 alkoxy group which may be branched such as a methoxy group and an ethoxy group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Examples of the lower alkyl group represented by R4 or R5 include a methyl group, an ethyl group, a propyl group, and an isopropyl group. Preferable examples of the alkoxyl group represented by R6 include a C1-C5 alkoxyl group which may be branched such as a methoxy group and an ethoxy group; and preferable examples of the alkyl group include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a propyl group.
Preferable examples of the integer shown by n include 1, 2, and 3.
When X is an oxygen atom, the substitution of X for the benzene ring is in an ortho, meta, or para position, preferably a para position.
When X is a methylene group, the substitution of X for the benzene ring is in an ortho, meta, or para position, preferably a meta or para position.
In the general formula (Ie): 
E, R3, R4, R5, R6, X, Y and n are as defined above, preferable examples of the halogen atom represented by R3 include a fluorine atom, a chlorine atom and a bromine atom; preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group and a trifluoromethyl group; and preferable examples of the alkoxyl group include a C1-C5 alkoxy group which may be branched such as a methoxy group and an ethoxy group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Examples of the lower alkyl group represented by R4 or R5 include a methyl group, an ethyl group, a propyl group, and an isopropyl group. Preferable examples of the alkoxyl group represented by R include a C1-C5 alkoxyl group which may be branched such as a methoxy group and an ethoxy group; and preferable examples of the alkyl group include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a propyl group.
Preferable examples of the integer shown by n include 1, 2, and 3.
When X is an oxygen atom, the substitution of X for the benzene ring is in an ortho, meta, or para position, preferably a para position.
When X is a methylene group, the substitution of X for the benzene ring is in an ortho, meta, or para position, preferably a meta or para position.
In the general formula (If): 
E, R3, R4, R5, R6, X, Y and n are as defined above, preferable examples of the halogen-atom represented by R3 include a fluorine atom, a chlorine atom and a bromine atom; preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group and a trifluoromethyl group; and preferable examples of the alkoxyl group include a C1-C5 alkoxy group which may be branched such as a methoxy group and an ethoxy group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Examples of the lower alkyl group represented by R4 or R5 include a methyl group, an ethyl group, a propyl group, and an isopropyl group. Preferable examples of the alkoxyl group represented by R6 include a C1-C5 alkoxyl group which may be branched such as a methoxy group and an ethoxy group; and preferable examples of the alkyl group include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a propyl group.
Preferable examples of the integer shown by n include 1, 2, and 3.
The substitution of X for the benzene ring is in an. ortho, meta, or para position, preferably a meta or para position.
In the general formula (Ig): 
R7 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group, R8 and R9 are the same or different from each other and represent a hydrogen atom, or an alkyl group, or R8 and R9 are taken together to represent a methylene group, R10 represents a hydrogen atom, a hydroxyl group, an alkoxy group or an:alkyl group, m is an integer from 0 to 6, and E, X and Y are as defined above, preferable examples of the halogen atom represented by R7 include a fluorine atom, a chlorine atom, and a bromine atom; preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group and a trifluoromethyl group; and preferable examples of the alkoxyl group include a C1-C5 alkoxy group which may be branched such as a methoxy group, and an ethoxy group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Preferable examples of the alkyl group represented by R8 or R9 include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a propyl group. Preferable examples of the alkoxy group represented by R10 include a C1-C5 alkoxy group, which may be branched such as a methoxy group and an ethoxy group; and preferable examples of the alkyl group include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a propyl group.
Preferable examples of the integer of 0 to 6 shown by m include 0, 1, 2, 3, and 4.
When X is an oxygen atom, the substitution of X for the benzene ring is in an ortho, meta, or para position, preferably a para position.
When X is a methylene group, the substitution of X for the benzene ring is in an ortho, meta or para position, preferably a meta or para position.
In the general formula (Ih): 
E, R7, R8, R9, R10, X, Y and m are as defined above, preferable examples of the halogen atom represented by R7 include a fluorine atom, a chlorine atom, and a bromine atom; preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group and a trifluoromethyl group; and preferable examples of the alkoxyl group include a C1 -C5 alkoxy group which may be branched such as a methoxy group, and an ethoxy group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Preferable examples of the alkyl group represented by R8 or R9 include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a propyl group. Preferable examples of the alkoxy group represented by R include a C1-C5 alkoxy group which may be branched such as a methoxy group and an ethoxy group; and preferable examples of the alkyl group include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a propyl group.
Preferable examples of the integer of 0 to 6 shown by m include 0, 1, 2, 3,and 4.
When X is an oxygen atom, the substitution of X for the benzene ring is in an ortho, meta or para position, preferably a para position.
When X is a methylene group, the substitution of X for the benzene ring is in an ortho, meta, or para position, preferably a meta or para position.
In the general formula (Ii): 
E, R7, R8, R9, R10, X, Y and m are as defined above, preferable examples of the halogen atom represented by R7 include a fluorine atom, a chlorine atom, and a bromine atom; preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group and a trifluoromethyl group; and preferable examples of the alkoxyl group include a C1-C5 alkoxy group which may be branched such as a methoxy group, and an ethoxy group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Preferable examples of the alkyl group represented by R8 or R9 include a C1-C5 alkyl group which maybe branched such as a methyl group, an ethyl group, and a propyl group. Preferable examples of the alkoxy group represented by R10 include a C1-C5 alkoxy group which may be branched such as a methoxy group and an ethoxy group; and preferable examples of the alkyl group include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a propyl group.
Preferable examples of the integer of 0 to 6 shown by m include 0, 1, 2, 3, and 4.
The substitution of X for the benzene ring is in an ortho, meta, or para position, preferably a meta or para position.
Among the compounds represented by the general formula (I), particularly preferable compounds are as follows: 
wherein, Ar represents a phenyl group and E, X, and Y are as defined above.
Further, the present invention provides compounds having the general formula (Ixe2x80x2) and their salts: 
wherein, Qxe2x80x2 represents a group having the formula:
Rxe2x80x2xe2x80x94Axe2x80x94Bxe2x80x94
in which Rxe2x80x2 represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group,
A represents a connecting bond, a cycloalkylene group, an alkenylene group which may be substituted by a lower alkyl group, a dialkoxymethylene group, or a hydroxyiminomethylene group, and
B represents an alkylene group which may be substituted by a hydroxy group or an alkoxy group;
a group having the formula: 
xe2x80x83in which R1 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group; or
a group having the formula:, 
xe2x80x83in which R2 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group,
X represents an oxygen atom or a methylene group, the substitution of X for the benzene ring is in an ortho, meta, or para position,
E and Y may be the same or different from each other and represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom,
the dotted line shows the presence or absence of a bond, when said dotted line shows the presence of a bond, Z represents a carbon atom, when said dotted line shows the absence of a bond, Z represents CH or a nitrogen atom,
when Z is a carbon atom or CH, X is a methylene group, A is a connecting bond, and B is an unsubstituted alkylene group, Rxe2x80x2 does not represent an unsubstituted phenyl group.
Preferable examples of substituent for the substituted or unsubstituted phenyl group, substituted or unsubstituted phenoxy group or substituted or unsubstituted benzoyl group represented by Rxe2x80x2 include a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom, a hydroxyl group, a C1-C5 alkoxy group which may be branched such as a methoxy group and an ethoxy group, a C1-C5 alkyl group which may be branched and may be substituted by a halogen atom such as a methyl group, an ethyl group and a trifluoromethyl group. Examples of the halogen atom of the C1-C5 alkyl group which may be branched and may be substituted by a, halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
The preferable examples of the cycloalkylene group, the alkenylene group which may be substituted by a lower alkyl group, or the dialkoxymethylene group represented by A, preferable examples of the alkylene group which may be substituted by a hydroxyl group or an alkoxy group represented by B, preferable examples of the halogen atom, the alkoxy group, or the alkyl group which may be substituted by a halogen atom represented by E or Y, and preferable examples of the halogen atom, the alkyl group which may be substituted by a halogen atom, and the alkoxy group represented by R1 or R2 are the same as with A, B, E, Y, R1 and R2 in the above general formula (I).
The present invention further provides compounds having the general formula (Ixe2x80x3) and their salts: 
wherein, Qxe2x80x2 represents a group having the formula:
Rxe2x80x2xe2x80x94Axe2x80x94Bxe2x80x94
in which Rxe2x80x2 represents a substituted or unsubstituted phenyl group, substituted or unsubstituted phenoxy group, for substituted or unsubstituted benzoyl group,
A represents a connecting bond, a cycloalkylene group, an alkenylene group which may be substituted by a lower alkyl group, a dialkoxymethylene group, or a hydroxyiminomethylene group, and
B represents a hydroxyl group- or alkoxyl group-substitutable an alkylene group which may be substituted by a hydroxyl group or an alkoxy group;
a group having the formula: 
xe2x80x83in which R1 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group; or
a group having the formula: 
xe2x80x83in which R2 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group,
X represents an oxygen atom or a methylene group, the substitution of X for the benzene ring is in an ortho, meta, or para position,
E and Y may be the same or different from each other and represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom,
the dotted line shows the presence or absence of a bond, and when X is a methylene group, A is a connecting bond and B is an unsubstituted alkylene group, Rxe2x80x2 does not represent an unsubstituted phenyl group.
The preferable examples of the substituent of the substituted or unsubstituted phenyl group, substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group represented by Rxe2x80x2, preferable examples of the cycloalkylene group, the alkenylene group which may be substituted by a lower alkyl group or the dialkoxymethylene group represented by A, preferable examples of the alkylene group which may be substituted by a hydroxyl group or an alkoxy group represented by B, preferable examples of the halogen atom, the alkoxy group, or the alkyl group which may be substituted by a halogen atom represented by E or Y, and preferable examples of the halogen atom, the alkyl group which may be substituted by a halogen atom, and the alkoxyl group represented by R6 or R7 are the same as with Rxe2x80x2, A, B, E, Y, R1 and R2 in the above general formula (Ixe2x80x2).
The compounds having the general formula (Ixe2x80x3) include the compounds having the general formulas (Ixe2x80x3a) and (Ixe2x80x3b)
In the general formula (Ixe2x80x3a): 
wherein, Qxe2x80x2, E, X, and Y are as defined above.
In the general formula (Ixe2x80x3b): 
wherein, Qxe2x80x2, E, X, and Y are as defined above.
The present invention further provides compounds having the general formula (Ixe2x80x2xe2x80x3) and their salts: 
herein, Qxe2x80x2 represents a group having the formula:
Rxe2x80x2xe2x80x94Axe2x80x94Bxe2x80x94
in which Rxe2x80x2 represents a substituted or unsubstituted phenyl group, substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group,
A represents a connecting bond, a cycloalkylene group, an alkenylene group which may be substituted by a lower alkyl group, a dialkoxymethylene group, or a hydroxyiminomethylene group and
B represents an alkylene group which may be substituted by a hydroxy group or an alkoxy group;
a group having the formula: 
xe2x80x83in which R1 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxyl group, or a hydroxyl group; or
a group having the formula: 
xe2x80x83in which R2 represents a hydrogen atom, a halogen atom, an alkyl group which may be substituted by a halogen atom, an alkoxy group, or a hydroxyl group,
X represents an oxygen atom or methylene group, the substitution of X for the benzene ring is in an ortho, meta, or para position, and
E and Y may be the same or different from each other and represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom-substitutable alkyl group.
The examples of the preferable substituent for the substituted or unsubstituted phenyl group, substituted or unsubstituted phenoxy group, or substituted or unsubstituted benzoyl group represented by Rxe2x80x2, preferable examples of the cycloalkylene group, the alkenylene group which may be substituted by a lower alkyl group, or the dialkoxymethylene group represented by A, preferable examples of the alkylene group which may be substituted by a hydroxyl group or alkoxyl group represented by B, preferable examples of the halogen atom, the alkoxy group, or the alkyl group which may be substituted by a halogen atom represented by E or Y and preferable examples of the halogen atom, the alkyl group which may be substituted by a halogen atom, or an alkoxy group represented by R1 or R2 are the same as with Rxe2x80x2, A, B, E, Y, R1 and R2 in the above general formula (Ixe2x80x2).
The compounds having the general formulas (I), (Ixe2x80x2), (Ixe2x80x3), and (Ixe2x80x2xe2x80x3) of the present invention include isomers. The present invention includes all of these isomers and mixtures of the same. For example, in the general formulas (I) (Ixe2x80x2), (Ixe2x80x3) and (Ixe2x80x2xe2x80x3), when B represents an alkylene group which may be substituted by a hydroxyl group or an alkoxyl group, there are two optical isomers, when A represents a hydroxyiminomethylene group and an alkenylene group which may be substituted by a lower alkyl group, there are two geometric isomers, (E)-form and (Z)-form. The compounds of the present invention include the individual isomers and all mixtures of combinations of the same.
According to the present invention, further, there are provided compounds of the general formula (IIa):
In the general formula (IIa): 
wherein, E and Y may be the same or different from each other and represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom, the dotted line shows the presence or absence of a bond, and the substitution of the benzene ring bonding with the piperidine ring or tetrahydropyridine ring and the group xe2x80x94OC6H4Y is in an ortho, meta, or para position.
According to the present invention, further, there are provided compounds having the general formula (IIb): 
wherein, E represents a hydrogen atom, hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom, Yxe2x80x2 represents a hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom, and the substitution of the benzene ring bonding with the tetrahydropyridine ring and group xe2x80x94CH2C6H4Yxe2x80x2 is in an ortho, meta, or para position.
According to the present invention, further, there are provided compounds having the general formula (IIc): 
wherein, E represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxyl group, or an alkyl group which may be substituted by a halogen atom, Yxe2x80x2 represents a hydroxyl group, a halogen atom, alkoxyl group, or an alkyl group which may be substituted by a halogen atom, and the substitution of the benzene ring bonding with the piperidine ring and the group xe2x80x94CH2C6H4Yxe2x80x2 is in a meta or para position.
According to the present invention, further, there are provided compounds having the general formula (IIIa): 
wherein, E and Y may be the same or different from each other and represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom.
According to the present invention, further, there are provided compounds having the general formula (IIIb): 
wherein, E and Y may be the same or different from each other and represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxyl group, or an alkyl group which may be substituted by a halogen atom.
The compounds. (Ia), (Id), (Ig) and (Ixe2x80x3a) in the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) wherein Z represents a carbon atom and the compounds (Ib), (Ie), (Ih) and (Ixe2x80x3b) wherein Z represents CH may be synthesized from compounds having the general formula (II): 
wherein, E and Y may be the same or different from each other and represent a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxy group, or an alkyl group which may be substituted by a halogen atom, and the dotted line shows the presence or absence of a bond.
The compounds (II) are explained by the general formulas (IId), (IIe), (IIf) and (IIg).
In the general formula (IId): 
wherein, E and Y are as defined above, preferable examples of the halogen atom represented by E or Y include a fluorine atom, a chlorine atom, and a bromine atom; preferable examples of the alkoxyl group include a C1-C5 alkoxy group which may be branched such as a methoxy group, and an ethoxy group; and preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a trifluoromethyl group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. The substitution of the benzene ring bonding with the tetrahydropyridine ring and the group OC6H4Y is in an ortho, meta, or para position, preferably a para position.
In the general formula (IIe): 
E and Y are as defined above, preferable examples of the halogen atom represented by E or Y include a fluorine atom, a chlorine atom, and a bromine atom; preferable examples of the alkoxyl group include a C1-C5 alkoxy group which may be branched such as a methoxy group, and an ethoxy group; and preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a trifluoromethyl group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. The substitution of the benzene ring bonding with the piperidine ring and the group xe2x80x94OC6H4Y is in an ortho, meta, or para position, preferably a para position.
In the general formula (IIf): 
E and Y are as defined above, preferable examples of the halogen atom represented by E or Y include a fluorine atom, a chlorine atom, and a bromine atom; preferable examples of the alkoxyl group include a C1-C5 alkoxy group which may be branched such as a methoxy group, and an ethoxy group; and preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, an ethyl group, and a trifluoromethyl group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. The substitution of the benzene ring bonding with the tetrahydropyridine ring and the group xe2x80x94CH2C6H4Y is in an ortho, meta, or para position, preferably meta or para position.
In the general formula (IIg): 
wherein, E and Y are as defined above, preferable examples of the halogen atom represented by E or Y include a fluorine atom, a chlorine atom, and a bromine atom; preferable examples of the alkoxyl group include a C1-C5 alkoxy group which may be branched such as a methoxy group, and an ethoxy group; and preferable examples of the alkyl group which may be substituted by a halogen atom include a C1-C5 alkyl group which may be branched such as a methyl group, methyl group, and a trifluoromethyl group. Examples of the halogen atom of the alkyl group which may be substituted by a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. The substitution of the benzene ring bonding with the piperidine ring and the group xe2x80x94CH2C6H4Y is in an ortho, meta, or para position, preferably meta or para position.
The compounds of the general formulas (I), (Ixe2x80x2), (Ixe2x80x3) or (Ixe2x80x2xe2x80x3), for example, may be synthesized in the following manners. These methods will be successively explained below.
The compounds. (Ia), (Id), (Ig), and (Ixe2x80x3a), (If) of the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) wherein Z represents a carbon atom and the compounds (Ib), (Ie), (Ih), and (Ixe2x80x3b), (Ig) wherein Z represents CH can be obtained as follows:
The compound (IIh) is obtained from a known starting material (IV).(step 1), then the compound (IIi) is obtained from the compound (IIh) (step 2). The compounds (Ia), (Id), (Ig), or (Ixe2x80x3a) can be obtained from the compound (IIh) (step 3) and the compound (Ib), (Ie), (Ih), or (Ixe2x80x3b) can be obtained from the compound (IIi) (step 4).
For compounds having the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) wherein A represents an alkenylene group, the compound (Ij) can be obtained from the compound (IIh) (step 5) and the compound (Ik) can be obtained from the compound (IIi) (step 6).
For compounds having the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) wherein B represents a hydroxyl group-substituted alkylene group, the compound (Il) can be obtained from the compound (IIh) (step 7) and the compound (Im) can be obtained from the compound (IIi) (step 8).
For compounds having the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) wherein B represents a methylene group, the compound (In) can be obtained from the compound (IIh) (step 9) and the compound (Io) can be obtained from the compound (IIi) (step 10).
Further, the compounds (Ic), (If), or (Ii) having the general formula (I) wherein Z represents a nitrogen atom or the compound (Ixe2x80x2xe2x80x3) having the general formula (Ixe2x80x2) wherein Z represents a nitrogen atom can be obtained from the known starting material (X) (step 11).
Step 1
The compound (IIh) can be synthesized in accordance with the following method from the known starting material (IV): 
wherein, E, X, and Y are as defined above, Exe2x80x2 and Yxe2x80x3 may be the same or different and represent a hydrogen atom, a halogen atom, alkoxyl group, or a halogen atom-substitutable alkyl group, and D represents a tert-butoxycarbonyl group, ethoxycarbonyl group, or acetyl group.
That is, the aryl bromide derivative having the general formula (IV) is converted by the conventional method to the corresponding aryl Grignard reagent or aryl lithium reagent, then is allowed to react in tetrahydrofuran, diethylether, ethyleneglycol dimethylether, toluene, or another solvent not participating in the reaction, at xe2x88x92100 to 50xc2x0 C., preferably xe2x88x9278xc2x0 C. to room temperature, with 1 to 1.5 equivalents of the known starting material N-tert-butoxycarbonyl-4-piperidone, N-ethoxy carbonyl-4-piperidone, or N-acetyl-4-piperidone for 1 to 6 hours so as to obtain the compound having the general formula (V).
The starting substance (IV) used in the reaction is a known compound as described in Martin et al. [L. Martin et al: J. Med. Chem., 22, 1347 (1979)] or can be synthesized by the similar method. For example, 4-bromodiphenylether, 4-bromophenylether, 2-bromodiphenylmethane, 3-bromo-diphenylmethane, 4-bromodiphenylmethane, 2-bromo-4xe2x80x2-fluorodiphenylmethane, 3-bromo-4xe2x80x2-fluorodiphenylmethane, 4-bromo-4xe2x80x2-fluorodiphenylmethane, 2-bromo-4xe2x80x2-chloro-diphenylmethane, 3-bromo-4xe2x80x2-chlorodiphenylmethane, 4-bromo-4xe2x80x2-chlorodiphenylmethane, 2-bromo-4xe2x80x2-methoxy-diphenylmethane, 3-bromo-4xe2x80x2-methoxydiphenylmethane, 4-bromo-4xe2x80x2-methoxydiphenylmethane, 2-bromo-4xe2x80x2-trifluoro-methyldiphenylmethane, 3-bromo-4xe2x80x2-trifluoromethyl-diphenylmethane, 4-bromo-4xe2x80x2-trifluoromethyl-diphenylmethane, 3-bromo-4-fluorodiphenylmethane, 3-bromo-4,4xe2x80x2-difluorodiphenylmethane, 3-bromo-4-fluoro-4xe2x80x2-chlorodiphenylmethane, 3-bromo-4-fluoro-4xe2x80x2-methoxy-diphenylmethane, 3-bromo-4xe2x80x2-fluoro-4xe2x80x2-trifluoromethyl-diphenylmethane, 3-bromo-4-methoxydiphenylmethane, 3-bromo-4-methoxy-4xe2x80x2-fluorodiphenylmethane, 3-bromo-4-methoxy-4xe2x80x2-chlorodiphenylmethane, 3-bromo-4,4xe2x80x2-dimethoxy-diphenylmethane, 3-bromo-4-methoxy-4xe2x80x2-trifluoromethyl-diphenylmethane, 5-bromo-2-methoxydiphenylmethane, 5-bromo-2-methoxy-4xe2x80x2-fluorodiphenylmethane, 5-bromo-2-methoxy-4xe2x80x2-chlorodiphenylmethane, 5-bromo-2,4,xe2x80x2-dimethoxy -diphenylmethane, 5-bromo-2-methoxy-4xe2x80x2-trifluoromethyl-diphenylmethane, and the like may be used. Further, as the conditions for preparing the Grignard reagent and the organolithium reagent, use may be made of the various methods described in the xe2x80x9cCompendium for Organic Synthesisxe2x80x9d (Wiley-Interscience: A Division of John Wiley and Sons Ltd.) etc.
The compound obtained from the reaction can be used as is for the next step or if necessary can be used after purification by a generally used purification method such as recrystallization or column chromatography.
Next, the compound (V) thus obtained is treated under non-solvent conditions or in tetrahydrofuran,. diethyl ether, ethyleneglycol dimethylether, benzene, toluene, methylene chloride, chloroform, carbon tetrachloride, water, methanol, ethanol, or another solvent not participating in the reaction, at xe2x88x9220 to 150xc2x0 C., preferably 0 to 80xc2x0 C., with 1 to 20 equivalents of organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and the like or inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and the like for 1 to 12 hours, or the compound (V) is let to react in benzene, toluene, methylene chloride, chloroform, carbon tetrachloride, or another solvent not participating in the reaction, if necessary in the presence of triethylamine, pyridine, diisopropylethylamine, or other bases, at xe2x88x9220 to 150xc2x0 C., preferably 0 to 100xc2x0 C., with 1 to 5 equivalents of thionylchloride, methane sulfonylchloride, trifluoromethane sulfonylchloride, trifluoromethanesulfonic acid anhydride, p-toluene sulfonylchloride, phosphorus oxychloride, or other acid chloride derivatives for 1 to 6 hours, then performing an acid treatment similar to the above, so as to obtain a compound having the general formula (IIh). Further, compounds having the general formula (IIh) wherein E or Y represents a hydroxyl group can be obtained by dealkylating a compound having the general formula (IIh) wherein E or Y represents an alkoxy group using the various methods described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (T. W. Greene, John Wiley and Sons Ltd.) etc.
The compound (IIh) obtained in step 1 can be reduced to synthesize the compound (IIi): 
(wherein, E, X, and Y are as defined above.)
That is, the compound (IIh) obtained in step 1 can be hydrogenated in the presence of palladium carbon, platinum, or another catalyst in methanol, ethanol, ethyl acetate, or another solvent not participating in the reaction at room temperature so as to convert it to the, compound having the general formula (IIi). Further, in the present reaction, if necessary, acetic acid, hydrochloric acid, or another acid may be added.
The compound (IIh) obtained in step 1 can be reacted with the compound (VI) or (VIxe2x80x2) to synthesize the compounds (Ia), (Id), (Ig), or (Ixe2x80x3a) having the general formula (I), (Ixe2x80x2) and (Ixe2x80x3) wherein Z is a carbon atom. 
(wherein, Q, Qxe2x80x2, E, X, Y, R3, R4, R5, R6, R7, R8, R9, R10, m, and n are as defined above, and w represents a group able to be easily exchanged with an amine group).
That is, the compound (IIh) obtained in step 1 may be allowed to react in tetrahydrofuran, diethylether, ethyleneglycol dimethylether, dioxane, acetonitrile, benzene, toluene, dimethylformamide, dimethylsulfoxide, or another solvent not participating in the reaction, in the presence of triethylamine, diisopropylethylamine, pyridine, or another organic base or sodium, potassium, sodium hydride, potassium hydride, sodium amide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, or other inorganic bases, at xe2x88x9220 to 150xc2x0 C., preferably room temperature to 100xc2x0 C., with 1 to 1.5 equivalents of the compound (VI) or (VIxe2x80x2) for 1 to 24 hours so as to obtain the tetrahydropyridine derivative of the general formula (Ia), (Id), (Ig), or (Ixe2x80x3a). Further, in the present reaction, if necessary, sodium iodide or tetrabutyl-ammonium iodide may be added.
W is a leaving group capable of being easily exchanged with an amine group and for example is a chlorine atom, bromine atom, or other halogen atom, alkylsulfonyloxy group such as a methane sulfonyloxy group or arylsulfonyloxy group such as a p-toluene sulfonyloxy group.
As the compound (VI) or (VII) usable in the present reaction, a commercially available or known compound may be used, for example, methyl iodide, ethyl iodide, ethyl bromide, propyl bromide, cinnamyl bromide, 3-bromo-2-methyl-1-phenyl-1-propene, 4-fluorocinnamyl bromide, (2,3,4-trimethoxy)cinnamyl bromide, 1-bromo-3-phenylpropane, (1-bromoethyl)benzene, (2-bromoethyl)benzene, 4-methoxycinnamyl bromide, 2-(4-fluorophenyl)oxyethyl bromide, 2-phenyloxyethyl bromide, 4-(4-fluorophenyl)oxybutyl bromide, 4-phenyloxybutyl bromide, 2-phenyloxypropyl bromide, trans-(2-phenyl) cyclopropylmethyl bromide, 1-phenyl-1-cyclopropylmethyl bromide, 1-phenyl-1-cyclopropanemethyl bromide, 1-phenyl-1-cyclopentanemethyl bromide, phenacyl bromide, 2-bromo-4xe2x80x2-methoxyacetophenone, 2-bromo-4xe2x80x2-fluoroacetophenone, 2-bromo-4xe2x80x2-chloroacetophenone, 2-bromopropiophenone, 2-bromo-2xe2x80x2,4xe2x80x2-dimethoxyacetophenone, 2-bromo-2xe2x80x2,5xe2x80x2-dimethoxyacetophenone, 2-bromo-4xe2x80x2-methylacetophenon, 4-chlorobutyrophenone, 4-chloro-4xe2x80x2-fluorobutyrophenone, 2-bromomethyl-2-phenyl-1,3-dioxolane, 2-bromomethyl-2-(4-fluorophenyl)-1,3-dioxolane, 2-bromomethyl-2-(4-chlorophenyl)-1,3-dioxolane, 2-bromomethyl-2-(4-methoxyphenyl)-1,3-dioxolane, 2-(1-bromoethyl)-2-phenyl-1,3-dioxolane, 2-bromomethyl-2-(4-methylphenyl)-1,3-dioxolane, 2-bromomethyl-2-(2,4-dimethoxyphenyl)-1,3-dioxolane, 2-bromomethyl-2-(2,5-dimethoxyphenyl)-1,3-d ioxolane, 2,3,4-trimethoxybenzylchloride, benzyl bromide, 4-fluorobenzyl bromide, 2-fluorobenzyl bromide, 3-fluorobenzyl bromide, 4-(trifluoromethyl)benzyl bromide, 2-(trifluoromethyl)benzyl bromide, 3-(trifluoromethyl) benzyl bromide, 2-bromo-1-indanone, 2-bromomethyl-benzofuran, (2-bromo-1-hydroxyiminoethyl)benzene, 3-methoxybenzyl chloride, 4-methoxybenzyl chloride, cinnamyl chloride, (2-bromo-1-methoxyethyl)benzene, 1-(4-chlorophenyl)cyclobutanemethyl bromide, 1-(4-chlorophenyl)cyclopentanemethyl bromide, 1-(4-methoxyphenyl) cyclopentanemethyl bromide, (2-brom6-1,1-diethoxy ethyl) benzene, etc. may be used.
Further, the compounds of the general formulas (Ia) and (Ixe2x80x3a) where A is a hydroxyiminomethylene group may be obtained by causing the corresponding ketone obtained in this step to react in pyridine, water, alcohol, water/alcohol or other solvent in the presence of pyridine, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassiumcarbonate or other base with hydroxyamine or its acid addition salt. Further, the compounds of the general formulas (Ia) and (Ixe2x80x3a) where B is a hydroxyl group-substituted alkylene group may be obtained by reducing the corresponding ketone obtained in this step by sodium borohydride, lithium aluminum hydride, aluminum dibutyl hydride, borane, and other metal reducing agents or by catalyzing hydrogenation in the presence of a catalytic amount of palladium carbon, platinum, etc.
The compound (VI) can be reacted with the compound (IIi) obtained in step 2 by a similar method as in step 3 to synthesize the compound (Ib): 
Compound (Ie): 
Compound (Ih): 
or Compound (Ixe2x80x3b): 
(wherein, Qxe2x80x2, E, X, Y, R3, R4, R5, R6, R7, R8, R9, R10, n, and m are as defined above) having the general formula (I), (Ixe2x80x2), and (Ixe2x80x3) where Z is CH.
The compounds (Ij) having the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) wherein A is an alkenylene group and Z is a carbon atom can be synthesized from the compound (IIh) obtained in step 1: 
(wherein, E, X, and Y are as defined above, and Rxe2x80x3 represents a substituted or unsubstituted phenyl group.)
That is, the compound (IIh) obtained at step 1 and the cinnamic acid derivative (VII) may be condensed by an ordinary method to convert to the amide derivative of the general formula (VIII), then reduced in tetrahydrofuran, diethylether, ethyleneglycol dimethylether, or another solvent not participating in the reaction at xe2x88x92100xc2x0 C. to 80xc2x0 C., preferably xe2x88x9278xc2x0 C. to room temperature, by 1 to 5 equivalents of lithium aluminum hydride or sodium bis(2-methoxyethoxy) aluminum hydride for 1 to 12 hours.
As the conditions of aforementioned amidation reaction, the various methods described in the xe2x80x9cCompendium for Organic Synthesisxe2x80x9d (Wiley-Interscience: A Division of John Wiley and Sons Ltd.)) etc. may be used. For example, the method of treating the cinnamic acid derivative (VII) if necessary in the presence of an organic or inorganic base with diethylphosphate cyanide (DEPC), diphenylphosphate adide (DPPA), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-iodo-1-methylpyridinium iodide, and the like may be used, or the cinnamic derivative (VII) may be made by an ordinary method into an acid halide, symmetric acid anhydride, mixed acid anhydride, or other active ester, etc., then condensed with the compound (IIh).
As the cinnamic acid derivative (VII) usable in the present reaction, a commercially available or known compound may be used, for example, cinnamic acid, 2,3,4-trimethoxycinnamic acid, xcex1-methylcinnamic acid, 4-hydroxy-3-methoxycinnamic acid, 3-hydroxy-4-methoxycinnamic acid, 4-chlorocinnamic acid, 3-chloro-cinnamic acid, 2-chlorocinnamic acid, 4-fluorocinnamic acid, 3-fluorocinnamic acid, 2-fluorocinnamic acid, 3,4,5-trimethoxycinnamic acid, 2-(trifluoromethyl)-cinnamic acid, 3-(trifluoromethyl)cinnamic acid, 4-(trifluoromethyl)cinnamic acid, 2-hydroxycinnamic acid, 3-hydroxycinnamic acid, 4-hydroxycinnamic acid, 2-methoxycinnamic acid, 3-methoxycinnamic acid, 4-methoxycinnamic acid, 2,6-difluorocinnamic acid, 2,4-difluorocinnamic acid, 2,5-difluorocinnamic acid, 3,4-difluorocinnamic acid, 3,5-difluorocinnamic acid, 2,6-dichlorocinnamic acid, 2,4-dichorocinnamic acid, 3,4-dichlorocinnamic acid, 2,3-dimethoxycinnamic acid, 2,4-dimethoxycinnamic acid, 2,5-dimethoxycinnamic acid, 3,4-dimethoxycinnamic acid, 3,4-(methylenedioxy)cinnamic acid, 3,5-dimethoxycinnamic acid, 3,4-dihydroxycinnamic acid, 3,4-dimethoxy-4-hydroxycinnamic acid, 2,4,5-trimethoxycinnamic acid, xcex1-methyl-2,4,5-trimethoxycinnamic acid, etc. may be used.
The compounds obtained in aforementioned reactions may be used as they are for the next step, but may also, be used after purification if necessary by a generally used purification method such as recrystallization or column chromatography etc.
The compounds (Ik) having the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) where A is an alkenylene group and Z is 
wherein E, Rxe2x80x3, X, and Y are as defined above can be synthesized from the compound (IIi) obtained in step 2 by the similar method as step 5.
The compounds (Il) having the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) where A is a connecting bond, B is a hydroxyl group-substituted alkylene group, and Z is a carbon atom: 
(wherein, l represents an integer of 0 or 1, and E, R, X, and Y are as defined above), can be synthesized from the compound (IIh) obtained at step 1.
That is, compound (IIh) obtained at step l may be allowed to react in tetrahydrofuran, diethylether, ethyleneglycol dimethylether, dioxane, acetonitrile, benzene, toluene, dimethylformamide, dimetlhylsulfoxide, methanol, ethanol, isopropylalcohol, tert-butylalcohol, ethyleneglycol, or another solvent not participating in the reaction, at room temperature to 200xc2x0 C., preferably 50xc2x0 C. to 150xc2x0 C., with 0.9 to 1.5 equivalents of the compound (IX) for 1 to 24 hours.
As the compound (IX) usable in the present reaction, a commercially available or known compound may be used, for example, 1,2-epoxyethylbenzene, (R)-(+)-1,2-epoxyethylbenzene, (S)-(xe2x88x92)-1,2-epoxyethylbenzene, (1R,2R)-(+)-1-phenylpropylene oxide, (1S,2S)-(xe2x88x92)-1-phenylpropylene oxide, 1,2-epoxy-3-phenylpropylene (K)-(xe2x88x92)-2-(benzyloxymethyl)oxirane, (S)-(+)-2-(benzyloxymethyl)oxirane, 2,3-epoxypropylbenzene, glycidyl 2-methylphenyl ether, 4-tert-butylphenyl 2,3-epoxypropyl ether, 4-chlorophenyl 2,3-epoxypropyl ether, 2,3-epoxypropyl 4-methoxyphenyl ether, etc. may be used.
Further, in the present reaction, if necessary, triethylamine, diisopropylethylamine, pyridine and other organic bases, sodium, potassium, sodium hydroxide, potassium hydroxide, sodium amide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, and other inorganic bases, or sodium iodide, tetrabutylammonium iodide, lithium carbonate, lithium chloride, zinc bromide, magnesium bromide, and other metal salts may be added alone or in combinations of a plurality of types.
Using the same method as in step 7, the compounds (Im) of the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) where A is a connecting bond, B is a hydroxyl group-substituted alkylene group, Z is CH: 
(wherein, l, E, R, X, and Y are as defined above) can be synthesized from the compound (III) obtained at step 2.
The compounds (In) of the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) wherein A is a connecting bond, B is a methylene group, and Z is a carbon atom can be synthesized from the compound. (IIh) obtained in step 1.
(wherein, E, Rxe2x80x3, X, and Y are as defined above.)
That is, the compound (IIh) obtained at step 1 and 1 to 1.2 equivalents of aldehyde (X) may be treated at room temperature to 200xc2x0 C., preferably 80 to 150xc2x0 C., while agitating, with 1 to 2 equivalents of formic acid to obtain the compound (In). Alternatively, the compound (IIh)and 1 to 1.2 equivalents of aldehyde may be treated in methanol, ethanol, isopropylalcohol, water, methanol/water or another solvent not participating in the reaction, if necessary adding sodium hydrogencarbonate, sodium dihydrogenphosphate, potassium dihydrogenphosphate, or aqueous solutions of the same, at xe2x88x9220 to 50xc2x0 C., preferably 0xc2x0 C. to room temperature, by 0.3 to 2 equivalents of sodium cyanoborohydride to obtain the compound (In).
As the compound (X) usable in the present reaction, a commercially available or known compound may be used, for example, benzaldehyde, 2-fluorobenzaldehyde, 2-chlorobenzaldehyde, o-anisaldehyde, m-anisaldehyde, p-anisaldehyde, xcex1,xcex1,xcex1-trifluoro-o-tolualdehyde, xcex1,xcex1,xcex1-trifluoro-m-tolualdehyde, xcex1,xcex1,xcex1-trifluoro-p-tolualdehyde, 3-fluorobenzaldehyde, 3-chlorobenzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, o-tolualdehyde, m-tolualdehyde, p-tolualdehyde, 3-fluoro-2-methylbenzaldehyde, 2-fluoro-3-(trifluoromethyl) benzaldehyde, 3,4-difluorobenzaldehyde, 2,3-difluorobenzaldehyde, 3-fluoro-p-anisaldehyde, 2,4-dimethoxybenzaldehyde, 2,5-dimethoxybenzaldehyde, 3,4-dimethoxybenzaldehyde, piperonal, 1,4-benzodioxane-6-carbaldehyde, 3,5-bis(trifluoromethyl)benzaldehyde, 3,5-dimethoxybenzaldehyde, 2,3-dimethyl-p-anisaldehyde, 2,3,4-trimethoxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 2,4,5-trimethoxybenzaldehyde, 2,4,6-trimethoxybenzaldehyde, etc. may be used.
Using the similar method as in step 9, the compound (Io) of the general formulas (I), (Ixe2x80x2), and (Ixe2x80x3) wherein A is a connecting bond, B is a methylene group, and Z is CH: 
wherein, E, Rxe2x80x3, X, and Y are as defined above can be synthesized from the compound (IIi) obtained in step 2.
The compounds (Ic), (If), or (Ii) having the general formula (I) wherein Z is a nitrogen atom or the compound (Ixe2x80x2xe2x80x3) having the general formula (Ixe2x80x2) wherein Z is a nitrogen atom: 
(wherein, Q, Qxe2x80x2, E, Exe2x80x2, X, Y, Yxe2x80x3, R3, R4, R5, R6, R7, R8, R9, R10, n, and m are as defined above) can be synthesized from the known starting material (X I).
That is, by causing the aniline derivative having the general formula (XI) to react under non-solvent conditions or in n-butanol, tert-butylalcohol or another solvent not participating in the reaction at 80xc2x0 C. to 300xc2x0 C., preferably 150xc2x0 C. to 250xc2x0 C., with 1 to 1.5 equivalents of a known bis-2-chloroethylamine hydrochloride for 1 to 12 hours, the compound of the general formula (III) can be obtained.
The starting material (XI) usable in the present reaction may be a compound which is commercially available or known through the literature [K. Suzuki et al.: J. Org. Chem., 26, 2239 (1961)] or may be synthesized by a known method as described for example in Japanese Examined Patent Publication (Kokoku) No. 6-25191. For example, 2-phenoxyaniline, 3-phenoxyaniline, 4-phenoxyaniline, 2-benzylaniline, 4-benzylaniline, 4-(4-fluorophenyl)methylaniline, 2-(4-fluorophenyl)-methylaniline, 4-(4-methoxyphenyl)methylaniline, 2-(4-methoxyphenyl)methylaniline, 4-(4-chlorophenyl)-methylaniline, 2-(4-chlorophenyl)methylaniline, 4-(4-trifluorophenyl)methylaniline, 2-(4-trifluorophenyl)-methylaniline, 2-benzyl-5-methoxyaniline, 4-benzyl-3-methoxyaniline, 2-(4-fluorophenyl) methyl-5-methoxyaniline, 4-(4-fluorophenyl) methyl-3-methoxyaniline, 5-fluoro-2-(4-fluorophenyl) methylaniline, 3-fluoro-4-(4-fluorophenyl) methylaniline, 5-fluoro-2-(4-methoxyphenyl) methylaniline, 3-fluoro-4-(4-methoxyphenyl) methylaniline, 5-methoxy-2-(4-methoxyphenyl)methylaniline, 3-methoxy-4-(4-methoxyphenyl)methylaniline, etc. may be used.
Further in the reaction according to the present invention, if necessary, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate or other inorganic bases may be added.
Further, the compound having the general formula (III) wherein E or Y is a hydroxyl group may be obtained by removing the protective group from the compound having the general formula (III) where E or Y is an alkoxy group using the various methods described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (T. W. Greene, John Wiley and Sons Ltd.) etc.
The compound (III) obtained in the aforementioned reaction can be used as it is for the next step, but can also be used after purification if necessary by a generally used purification method such as recrystallization or column chromatography etc.
The resultant compound (III) can be converted to the aryl piperadine derivatives having the general formulas, (Ic), (If), (Ii), or (Ixe2x80x2xe2x80x3) by treating the said compound by the same methods as in, step 3, step 5, step 7, or step 9.
The isomers included in the compounds having the general formulas (I), (Ixe2x80x2), (Ixe2x80x3), and (Ixe2x80x2xe2x80x3) of the present invention may be separated by ordinary methods, for example, recrystallization, column chromatography, thin layer chromatography, high pressure liquid chromatography, or the similar methods using optically active reagents.
The compound having general formulas (I), (Ixe2x80x2), (Ixe2x80x3), and (Ixe2x80x2xe2x80x3) according to the present invention may be dissolved in a suitable organic solvent, for example, ether, tetrahydrofuran, methylene chloride, chloroform, benzene, toluene, etc. and treated by an inorganic or organic acid to obtain the corresponding salt. The inorganic acid used here include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, periodic acid, and the like and the organic acid include formic acid, acetic acid, lactic acid, oxalic acid, malonic acid, propionic acid, valeric acid, succinic acid, fumaric acid, maleic acid, citric acid, malic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, and the like.
The compounds having the general formula (I), (Ixe2x80x2), (Ixe2x80x3) and (Ixe2x80x2xe2x80x3) of the present invention are low in toxicity and can be used alone by themselves or if desired can be prepared with other normal pharmaceutically allowable known and generally used carriers into preparations designed for the alleviation and treatment of symptoms based on ischemic diseases and symptoms derived from seizures, epilepsy, and migraine. For example, the effective ingredient can be administered orally or nonorally by itself or made into a capsule, tablet, injection, or other suitable preparation together with usually used excipients. For example, capsule preparations are prepared by mixing the powder with lactose, starch or its derivatives, cellulose derivatives or other excipients and packing the mixture into gelatin capsules. Further, tablets can be prepared by adding and kneading in, in addition to said excipient, sodium carboxycarboxymethylcellulose, alginic acid, arabia gum, and other binders and water, if necessary granulating the same, then further adding talc, stearic acid, and other lubricants and preparing the final form using a usual compression tablet-making machine. At the time of non-oral administration using injection, the effective ingredient is dissolved together with a solubilizer in sterilized distilled water or sterilized physiological saline and sealed in an ampule to make the injection preparation. If necessary, a stabilizing agent, buffer, etc. may also be included.
The dosage of the medicine for alleviation or treatment of symptoms based on ischemic diseases and symptoms derived from seizures, epilepsy and migraine of the present invention depends on various factors, for example, the symptoms and age of the patient to be treated, the route of administration, the form of the preparation, the frequency of administration, etc., but usually is 0.1 to 1000 mg/day/person, preferably 1 to 500 mg/day/person.